Many factors, including pathogens, environmental change and breeding techniques, affect honeybee immunity/resistance, so substances and natural supplements that enhance it are desired. To eliminate the impact of unknown external factors, in 2016 a cage experiment was conducted under constant laboratory conditions (35 °C, 65% relative humidity). Bees in the control group were fed with sugar dissolved in water at ratio 1:1 ad libitum with no additives, while the other group was fed with sugar syrup (1:1) supplemented with piperine (3 µg/ml) ad libitum. The piperine-treated workers lived 9 days longer compared to the control group. In the piperine-consuming group, protein concentration and the activities of antioxidative enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione S-transferase (GST), were higher than in the control group. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were also higher in the piperine-treated group. Neutral and acidic proteases inhibitors, as well as neutral protease activities, were higher in the haemolymph of the piperine-treated workers than in untreated bees. Acidic protease activities in the haemolymph were higher in untreated workers only on days 18 and 32. Alkaline protease activities in the control bees were higher from day 10. From 10 days old, the total antioxidant capacity level was significantly higher in the haemolymph of piperine-treated workers. Piperine decreased DNA methylation levels significantly in the older bees. The compound could have the potential to be a natural diet supplement increasing apian resistance to stress factors.